The myeloproliferative neoplasms (MPN), originate at the level of the pluripotent hematopoietic stem cell. Each MPN can undergo clonal evolution and hematologic progression that terminates in bone marrow failure, marked by progressive man'ow fibrosis, extramedullary hematopoiesis, and/or transfonnation to acute leultemia (AL). The leading causes of morbidity and mortality in PV and ET are thrombotic complications, followed by myelofibrosis and AL. PMF has a much graver prognosis due to marrow failure, the development of massive hepato-splenomegaly and a higher rate of transformation to AL. The somatic mutation JAK2 V617F, present in between 30-95% of patients with MPN, confers constitutive tyrosine kinase activity and plays a role in the pathophysiology of MPN. MPN have not been the subject of an organized group of investigators focused on studying their pathophysiology in a manner which would lead to the development of translational clinical trials since the demise of the P Vera Study Group two decades ago. Although individual investigators have conducted clinical trials and two multi-institutional phase III studies have been completed establishing the efficacy of aspirin in reducing risk of thrombosis, and the utility of hydroxyurea in the long term in patients with ET none of these treatments has changed the natural history of the MPN. We have established the Myeloproliferative Disorders Research Consortium (MPD-RC) an intemationai group of 24 academic centers in the US and Europe to conduct translational clinical trials in MPN. The goals of this project are to conduct a series of hypothesis driven MPD-RC investigator initiated translational clinical trials, based on interactions with the laboratory based projects in the MPD-RC, in order to identify active new agents and approaches that alone or in combination, can change both the treatment paradigm and natural history of the MPN leading to improved outcomes for such patients. The specific aims include plans to conduct phase l/ll trials in patients with PMF testing such novel approaches as: CEP 701, a JAK2 inhibitor; azacitidine and vorinostat an epigenetic approach to disease modification based on observations made in Project 5: plitidepsin an inhibitor of protein tyrosine phosphatases known to change the natural history of MF in a Gata(low)' mouse model developed in project 4, and allogeneic stem cell transplant as a potential curative approach. In PV, the effects of pegylated interferon alpha-2a as well as anti-thrombotic agents will be studied in high risk PV and ET in phase 2/3 trials. These investigator initiated trials are completely dependent on the clinical research infrastructure of the MPD-RC